PROJECT SUMMARY: Non-melanoma skin cancers (NMSC), which include basal cell carcinomas (BCC) and squamous cell carcinomas (SCC), are the most commonly diagnosed cancers with over a million new cases annually in the US. Of the main NMSC subtypes, SCC has a greater risk for metastasis and mortality. While the mortality rate is not as high for SCC compared to some other cancer types, there are very few effective non-surgical interventions. As a result, SCC can lead to significant morbidity and financial burden for patients. One of the most important risk factors for SCC development is ultraviolet light (UV) exposure from the sun. UV damages the DNA, leading to mutations in epithelial keratinocytes on the surface of the skin and consequently, to the formation of tumors. Additionally, UV exposure induces a robust cutaneous inflammatory response, and inflammation has been shown by our group as well as others to drive skin carcinogenesis. Recently, the function of the relatively newly described cytokine, IL-33, has started to be described in the skin. Several studies in addition to preliminary data included in this application have shown that IL-33 stimulates inflammation in the skin. Furthermore, recently published data and our preliminary results show that IL-33 expression is upregulated in keratinocytes after UV exposure during times of peak inflammation. Our preliminary data also show that IL-33 is expressed by tumor cells in both murine and human skin tumors. Thus far, there is very little information about the role of IL-33 in any cancer type, including the skin; however, based on its upregulation by UV and its demonstrated role in cutaneous inflammation, IL-33 is likely to be a key mediator of skin carcinogenesis. The central hypothesis of the proposed studies is that IL-33 promotes skin carcinogenesis by altering UV- induced inflammation. The following Specific Aims will be carried out to test this hypothesis: Aim 1 - Examine the function of IL-33 in UV-induced inflammation; Aim 2 - Determine the importance of IL-33 in UV-induced skin carcinogenesis. Overall, these experiments will generate valuable new information about IL-33 in the development and growth of SCC and will be the first steps in determining whether it is logical to develop treatment strategies aimed at blocking the effects of IL-33. .